CN1376160A - Novel macrolide antibiotics - Google Patents
Novel macrolide antibiotics Download PDFInfo
- Publication number
- CN1376160A CN1376160A CN99812941A CN99812941A CN1376160A CN 1376160 A CN1376160 A CN 1376160A CN 99812941 A CN99812941 A CN 99812941A CN 99812941 A CN99812941 A CN 99812941A CN 1376160 A CN1376160 A CN 1376160A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- aryl
- methyl
- heteroaryl
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003120 macrolide antibiotic agent Substances 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 144
- 238000000034 method Methods 0.000 claims abstract description 87
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 206010037075 Protozoal infections Diseases 0.000 claims abstract description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 208000015181 infectious disease Diseases 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 11
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 110
- 239000001257 hydrogen Substances 0.000 claims description 110
- 125000000217 alkyl group Chemical group 0.000 claims description 107
- 125000001072 heteroaryl group Chemical group 0.000 claims description 96
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 82
- -1 Sulfonamido Chemical group 0.000 claims description 80
- 125000003118 aryl group Chemical group 0.000 claims description 79
- 229910052736 halogen Inorganic materials 0.000 claims description 58
- 150000002367 halogens Chemical class 0.000 claims description 58
- 229910052760 oxygen Inorganic materials 0.000 claims description 55
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 54
- 125000003545 alkoxy group Chemical group 0.000 claims description 49
- 239000001301 oxygen Substances 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 43
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 38
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 37
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 36
- 125000003342 alkenyl group Chemical group 0.000 claims description 36
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 34
- 241000894006 Bacteria Species 0.000 claims description 33
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 26
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 26
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 241000283690 Bos taurus Species 0.000 claims description 21
- 241000191967 Staphylococcus aureus Species 0.000 claims description 20
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 241000606856 Pasteurella multocida Species 0.000 claims description 15
- 229940051027 pasteurella multocida Drugs 0.000 claims description 15
- 241000251468 Actinopterygii Species 0.000 claims description 14
- 241000271566 Aves Species 0.000 claims description 14
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 14
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 14
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 14
- 241000588724 Escherichia coli Species 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Natural products O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 10
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 241000606768 Haemophilus influenzae Species 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 10
- 241000193403 Clostridium Species 0.000 claims description 9
- 241000282326 Felis catus Species 0.000 claims description 9
- 208000016604 Lyme disease Diseases 0.000 claims description 9
- 241000606860 Pasteurella Species 0.000 claims description 8
- 241000193985 Streptococcus agalactiae Species 0.000 claims description 8
- 229960003276 erythromycin Drugs 0.000 claims description 8
- 229940030998 streptococcus agalactiae Drugs 0.000 claims description 8
- 108010065152 Coagulase Proteins 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 241001312524 Streptococcus viridans Species 0.000 claims description 7
- 201000011510 cancer Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 241000589968 Borrelia Species 0.000 claims description 6
- 241001647372 Chlamydia pneumoniae Species 0.000 claims description 6
- 241000606153 Chlamydia trachomatis Species 0.000 claims description 6
- 241000186367 Mycobacterium avium Species 0.000 claims description 6
- 241000588652 Neisseria gonorrhoeae Species 0.000 claims description 6
- 241000191992 Peptostreptococcus Species 0.000 claims description 6
- 208000019802 Sexually transmitted disease Diseases 0.000 claims description 6
- 206010062255 Soft tissue infection Diseases 0.000 claims description 6
- 241000191963 Staphylococcus epidermidis Species 0.000 claims description 6
- 241000282898 Sus scrofa Species 0.000 claims description 6
- 229940038705 chlamydia trachomatis Drugs 0.000 claims description 6
- 208000023504 respiratory system disease Diseases 0.000 claims description 6
- 201000009890 sinusitis Diseases 0.000 claims description 6
- 208000011580 syndromic disease Diseases 0.000 claims description 6
- 208000019206 urinary tract infection Diseases 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 241000223935 Cryptosporidium Species 0.000 claims description 5
- 241000588655 Moraxella catarrhalis Species 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 241000191940 Staphylococcus Species 0.000 claims description 4
- 241000191984 Staphylococcus haemolyticus Species 0.000 claims description 4
- CVBHEIRZLPKMSH-SNWVVRALSA-N erythromycin acistrate Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(C)=O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 CVBHEIRZLPKMSH-SNWVVRALSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229940037649 staphylococcus haemolyticus Drugs 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 4
- 241000606750 Actinobacillus Species 0.000 claims description 3
- 241000588986 Alcaligenes Species 0.000 claims description 3
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 3
- 208000020350 Bacteroides infectious disease Diseases 0.000 claims description 3
- 241001518086 Bartonella henselae Species 0.000 claims description 3
- 241000588807 Bordetella Species 0.000 claims description 3
- 241000588832 Bordetella pertussis Species 0.000 claims description 3
- 241000589875 Campylobacter jejuni Species 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 241000193468 Clostridium perfringens Species 0.000 claims description 3
- 206010010741 Conjunctivitis Diseases 0.000 claims description 3
- 208000031973 Conjunctivitis infective Diseases 0.000 claims description 3
- 241000186031 Corynebacteriaceae Species 0.000 claims description 3
- 241000186216 Corynebacterium Species 0.000 claims description 3
- 206010011224 Cough Diseases 0.000 claims description 3
- 206010011844 Dacryocystitis Diseases 0.000 claims description 3
- 241000605721 Dichelobacter nodosus Species 0.000 claims description 3
- 241000305071 Enterobacterales Species 0.000 claims description 3
- 241000186394 Eubacterium Species 0.000 claims description 3
- 206010016952 Food poisoning Diseases 0.000 claims description 3
- 208000019331 Foodborne disease Diseases 0.000 claims description 3
- 241000605909 Fusobacterium Species 0.000 claims description 3
- 241000605975 Fusobacterium varium Species 0.000 claims description 3
- 201000000628 Gas Gangrene Diseases 0.000 claims description 3
- 208000005577 Gastroenteritis Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- 206010019375 Helicobacter infections Diseases 0.000 claims description 3
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 3
- 241001148567 Lawsonia intracellularis Species 0.000 claims description 3
- 241000589248 Legionella Species 0.000 claims description 3
- 208000007764 Legionnaires' Disease Diseases 0.000 claims description 3
- 208000010315 Mastoiditis Diseases 0.000 claims description 3
- 241000186364 Mycobacterium intracellulare Species 0.000 claims description 3
- 241001138504 Mycoplasma bovis Species 0.000 claims description 3
- 206010028470 Mycoplasma infections Diseases 0.000 claims description 3
- 241000202934 Mycoplasma pneumoniae Species 0.000 claims description 3
- 241000231286 Neottia Species 0.000 claims description 3
- 206010031252 Osteomyelitis Diseases 0.000 claims description 3
- 206010033078 Otitis media Diseases 0.000 claims description 3
- 206010034107 Pasteurella infections Diseases 0.000 claims description 3
- 201000007100 Pharyngitis Diseases 0.000 claims description 3
- 206010035664 Pneumonia Diseases 0.000 claims description 3
- 241000605894 Porphyromonas Species 0.000 claims description 3
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 3
- 206010036600 Premature labour Diseases 0.000 claims description 3
- 241000605861 Prevotella Species 0.000 claims description 3
- 206010057190 Respiratory tract infections Diseases 0.000 claims description 3
- 241000607142 Salmonella Species 0.000 claims description 3
- 206010040070 Septic Shock Diseases 0.000 claims description 3
- 241000270295 Serpentes Species 0.000 claims description 3
- 241000295644 Staphylococcaceae Species 0.000 claims description 3
- 241001221452 Staphylococcus faecalis Species 0.000 claims description 3
- 241000191980 Staphylococcus intermedius Species 0.000 claims description 3
- 241001147691 Staphylococcus saprophyticus Species 0.000 claims description 3
- 206010061372 Streptococcal infection Diseases 0.000 claims description 3
- 241000194042 Streptococcus dysgalactiae Species 0.000 claims description 3
- 241000194054 Streptococcus uberis Species 0.000 claims description 3
- 206010044248 Toxic shock syndrome Diseases 0.000 claims description 3
- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 3
- 208000025865 Ulcer Diseases 0.000 claims description 3
- 241000202921 Ureaplasma urealyticum Species 0.000 claims description 3
- 206010046793 Uterine inflammation Diseases 0.000 claims description 3
- 206010000269 abscess Diseases 0.000 claims description 3
- 201000001028 acute contagious conjunctivitis Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229940092524 bartonella henselae Drugs 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 235000013365 dairy product Nutrition 0.000 claims description 3
- 206010013023 diphtheria Diseases 0.000 claims description 3
- 208000001848 dysentery Diseases 0.000 claims description 3
- 208000010801 foot rot Diseases 0.000 claims description 3
- 208000028774 intestinal disease Diseases 0.000 claims description 3
- 230000000968 intestinal effect Effects 0.000 claims description 3
- 206010023332 keratitis Diseases 0.000 claims description 3
- 229940045505 klebsiella pneumoniae Drugs 0.000 claims description 3
- 208000004396 mastitis Diseases 0.000 claims description 3
- 210000000214 mouth Anatomy 0.000 claims description 3
- 230000002688 persistence Effects 0.000 claims description 3
- 208000026440 premature labor Diseases 0.000 claims description 3
- 201000003068 rheumatic fever Diseases 0.000 claims description 3
- 206010040872 skin infection Diseases 0.000 claims description 3
- 229940115920 streptococcus dysgalactiae Drugs 0.000 claims description 3
- 229940115922 streptococcus uberis Drugs 0.000 claims description 3
- 206010044008 tonsillitis Diseases 0.000 claims description 3
- 239000003053 toxin Substances 0.000 claims description 3
- 231100000765 toxin Toxicity 0.000 claims description 3
- 231100000397 ulcer Toxicity 0.000 claims description 3
- 208000000143 urethritis Diseases 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Chemical group 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- 230000001580 bacterial effect Effects 0.000 abstract description 12
- 239000003904 antiprotozoal agent Substances 0.000 abstract description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- 238000006243 chemical reaction Methods 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000000243 solution Substances 0.000 description 42
- 230000008569 process Effects 0.000 description 41
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 30
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 25
- 239000002585 base Substances 0.000 description 25
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 239000003795 chemical substances by application Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 11
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 9
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 description 8
- 101100119095 Enterococcus faecalis (strain ATCC 700802 / V583) ermB gene Proteins 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- HEOKFDGOFROELJ-UHFFFAOYSA-N diacetal Natural products COc1ccc(C=C/c2cc(O)cc(OC3OC(COC(=O)c4cc(O)c(O)c(O)c4)C(O)C(O)C3O)c2)cc1O HEOKFDGOFROELJ-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 7
- 239000004202 carbamide Substances 0.000 description 7
- 235000013877 carbamide Nutrition 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- COXRPBBNPBCNDM-UHFFFAOYSA-N Dioxamide Natural products C1=C2OCOC2=CC(C=CC(=O)N(CCC=2C=C3OCOC3=CC=2)C)=C1 COXRPBBNPBCNDM-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 150000001447 alkali salts Chemical class 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 4
- 238000011203 antimicrobial therapy Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 235000013372 meat Nutrition 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 238000003752 polymerase chain reaction Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000008261 resistance mechanism Effects 0.000 description 4
- 238000013207 serial dilution Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 235000014347 soups Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 4
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 229910004298 SiO 2 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 150000002596 lactones Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 101150021123 msrA gene Proteins 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000003880 polar aprotic solvent Substances 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 2
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 2
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 101150052154 MSRA1 gene Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 229960004099 azithromycin Drugs 0.000 description 2
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 150000003818 basic metals Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 101150016744 ermC gene Proteins 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 235000015110 jellies Nutrition 0.000 description 2
- 239000008274 jelly Substances 0.000 description 2
- 239000004571 lime Substances 0.000 description 2
- 239000011981 lindlar catalyst Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 101150114366 msrA2 gene Proteins 0.000 description 2
- 101150006794 msrAB gene Proteins 0.000 description 2
- 101150109310 msrAB1 gene Proteins 0.000 description 2
- 101150052209 msrAB2 gene Proteins 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 235000012976 tarts Nutrition 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- SDGHXWKVBZYHRR-UHFFFAOYSA-N 2-(1h-imidazol-2-ylsulfonyl)-1h-imidazole Chemical compound N=1C=CNC=1S(=O)(=O)C1=NC=CN1 SDGHXWKVBZYHRR-UHFFFAOYSA-N 0.000 description 1
- LYTMVABTDYMBQK-UHFFFAOYSA-N 2-benzothiophene Chemical compound C1=CC=CC2=CSC=C21 LYTMVABTDYMBQK-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical class CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000224483 Coccidia Species 0.000 description 1
- 241001518260 Corynebacterium minutissimum Species 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101100240347 Mus musculus Nectin2 gene Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 241001147660 Neospora Species 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 description 1
- 229930182556 Polyacetal Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010015795 Streptogramin B Proteins 0.000 description 1
- 108010034396 Streptogramins Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- JJLXCWBAIHUBIW-UHFFFAOYSA-N [N-]=[N+]=[N-].[K+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] Chemical compound [N-]=[N+]=[N-].[K+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] JJLXCWBAIHUBIW-UHFFFAOYSA-N 0.000 description 1
- GARJITDFQFOYKD-UHFFFAOYSA-N [N-]=[N+]=[N-].[Li+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] Chemical class [N-]=[N+]=[N-].[Li+].[Si+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] GARJITDFQFOYKD-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 244000037640 animal pathogen Species 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical group 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 229940041028 lincosamides Drugs 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 101150111763 mefA gene Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- YGXCETJZBDTKRY-DZCVGBHJSA-N pristinamycin IA Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2CCC(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O YGXCETJZBDTKRY-DZCVGBHJSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical class [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 1
- 125000005306 thianaphthenyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- PCTNAMGLSYHIPL-UHFFFAOYSA-N tin(4+) tetraazide Chemical compound [Sn+4].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-].[N-]=[N+]=[N-] PCTNAMGLSYHIPL-UHFFFAOYSA-N 0.000 description 1
- 235000015149 toffees Nutrition 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
This invention relates to compounds of formula I wherein a, R<1>, R<2>, R<3>, R<4>, R<5>, R<6> and X are each as defined above, and to pharmaceutically acceptable salts thereof, useful as potent antibacterial and antiprotozoal agents that may be used to treat various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula I and to methods of treating bacterial and protozoal infections by administering the compounds of formula I.
Description
Background of invention
The present invention relates to new macrolide derivatives, can be used as the Mammals that comprises the people and antibacterium and the antiprotozoal of fish and birds.The present invention also relates to contain the pharmaceutical composition of this new compound, with bacterium and the protozoal infections of treatment Mammals, fish and birds and with infectation of bacteria the method for relevant illness, for example atherosclerosis and cancer, this method are Mammals, fish and the birds administrations to this treatment of needs of compound that this is new.
Known macrolide antibiotic can be used for the treatment of Mammals, fish and birds broad spectrum of bacteria and protozoal infections.Such microbiotic comprises the various derivatives of Erythromycin A, azithromycin for example, and it is commercial available, referring to United States Patent (USP) 4474768 and 4517359, the two quotes in full at this as a reference.As azithromycin and other macrolide antibiotic, new Macrocyclic lactone compounds of the present invention also is the wide spectrum macrolide antibiotic, effectively resists the infection that is caused by some Gram-positive and gram negative bacterium and protozoon.
Summary of the invention
The present invention relates to following formula: compound
Or its pharmacy acceptable salt; Wherein the dotted line between 10 and 11 is represented optional double bond; A is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be amino, cyano group, N
3, R
10NH, R
10C (O) NH, R
10NHC (O) NH, R
10NHC (S) NH, R
10NHNHC (O) NH, R
10ONHC (O) NH, R
10O, R
10OC (O) NH, R
10S (O)
n, R
10Phosphinylidyne amino, R
10Sulfonamido, SH, R
10S, n definition wherein is the same, R
10Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl; Perhaps R
3Be R
12R
13N, R wherein
12And R
13Be hydrogen, (C independently of one another
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl;
R
4Be hydrogen, optional by one or two nitro, cyano group, R
14C (O) and R
14The methyl that OC (O) replaces; Perhaps R
4Be N
3, R
14O, R
14NH, R
14S, R wherein
14Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl; Perhaps R
4Be R
15N (C
1-C
6) alkyl, R wherein
15Be hydrogen, (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl;
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
Wherein the dotted line between nitrogen in formula II and the variable group W is represented optional double bond;
W is C=O, C=S, SO
2Or C=NR
10, R wherein
10Define the same;
Y is oxygen, sulphur or NR
17, R wherein
17Be hydrogen, R
19, R
19O or R
19NH, R wherein
19Be hydrogen, (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
5-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
18Be hydrogen, (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, aryl wherein and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
20R
21N, R
20C (O), R
20C (O) O, R
20OC (O), R
20C (O) NH, R
20NHC (O), R
20R
21NC (O) and R
20OC (O)
2, R wherein
20And R
21Be hydrogen, optional quilt (C independently of one another
6-C
10) acyl group or (C
5-C
10) (the C that replaces of aryl
1-C
6) alkyl or (C
2-C
9) heteroaryl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement;
Its condition is R
17Or R
18Have at least one to be hydrogen;
If its condition is dotted line representative two key, then R between 10 and 11
4Be hydrogen;
Its condition is if a is zero, then R
1Be hydrogen.
Term used herein " alkyl " unless indication is arranged in addition, comprise have straight chain, the saturated monovalence alkyl of side chain or cyclic group.Self-evidently concerning cyclic group be, need at least three carbon atoms in described alkyl, self-evident concerning the described alkyl that comprises carbon-to-carbon double bond or three key is to need at least two carbon atoms in described alkyl.
Term used herein " hydroxy-protective group " comprises benzoyl, benzyl, (C unless indication is arranged in addition
1-C
6) alkyloyl, ((C
1-C
3) alkyl)
3Silyl and t-butyldimethylsilyl are preferably ethanoyl.Alkyloyl can cracking after as the prodrug administration.
Term used herein " aryl " comprises from aromatic hydrocarbons and removes a hydrogen and deutero-organic group, for example phenyl or naphthyl unless indication is arranged in addition.
(C used herein
2-C
9) Heterocyclylalkyl refers to pyrrolidyl, tetrahydrofuran base, the dihydrofuran base, THP trtrahydropyranyl, pyranyl, the thiapyran base, aziridinyl, Oxyranyle, methylene-dioxy, benzopyranyl isoxazole alkyl, 1,3-oxazolidine-3-base, the isothiazole alkyl, 1,3-thiazolidine-3-base, 1,2-pyrazolidine-2-base, 1,3-pyrazolidine-1-base, piperidyl, thio-morpholinyl, 1,2-tetrahydrochysene thiazine-2-base, 1,3-tetrahydrochysene thiazine-3-base, tetrahydrochysene thiadiazine base, morpholinyl, 1,2-tetrahydrochysene diazine-2-base, 1,3-tetrahydrochysene diazine-1-base, tetrahydrochysene azatropylidene base, piperazinyl, chromanyl etc.Those of ordinary skills will figure out, described (C
2-C
9) heterocycloalkyl ring is by carbon atom or sp
3The hydridization nitrogen heteroatom connects.
(C used herein
2-C
9) heteroaryl refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl oxazolyl isoxazolyl, pyrryl, triazolyl, tetrazyl, imidazolyl, 1,3,5-oxadiazole base, 1,2,4-oxadiazole base, 1,2,3-oxadiazole base, 1,3, the 5-thiadiazolyl group, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2, the 4-triazinyl, 1,2, the 3-triazinyl, 1,3, the 5-triazinyl, pyrazolo [3,4-b] pyridyl, the cinnolines base, pteridyl, purine radicals, 6,7-dihydro-5H-[1] indyl, benzo [b] thienyl, 5,6,7,8-tetrahydroquinoline-3-base benzoxazolyl, benzothiazolyl, the benzisothiazole base, the benzoisoxazole base, benzimidazolyl-, thianaphthenyl, the isothianaphthene base, benzofuryl, isobenzofuran-base, pseudoindoyl, indyl, the indolizine base, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolyl benzoxazinyl etc.Those of ordinary skills will figure out, described (C
2-C
9) heteroaryl ring is by carbon atom or sp
3The hydridization nitrogen heteroatom connects.
Term used herein " acyl group " comprises general formula R CO group unless indication is arranged in addition, and wherein R is alkyl, alkoxyl group, aryl, aralkyl or aralkoxy, and term " alkyl " or " aryl " definition are the same.
The compounds of this invention comprises all configurational isomers (for example cis and trans-isomer(ide)) and all optically active isomers (for example enantiomorph and diastereomer) of formula I compound, and the racemic mixture of these isomer, non-enantiomer mixture and other mixture.
Wording used herein " pharmacy acceptable salt " comprises the acidity that may reside in the The compounds of this invention or the salt of basic group unless indication is arranged in addition.The The compounds of this invention of alkalescence can form multiple salt with various inorganic and organic acids.The acid that can be used for preparing the pharmaceutically-acceptable acid addition of these basic cpds is to form those of nontoxic acid salt, promptly contain pharmaceutically acceptable anionic salt, hydrochloride for example, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, Citrate trianion, the acid Citrate trianion, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and pamoate (promptly 1,1 '-methylene radical-two (2-hydroxyl-3-naphthoate)).Except above-mentioned acid, comprise that the The compounds of this invention of amino group can also form pharmacy acceptable salt with each seed amino acid.
The tart The compounds of this invention can form alkali salt with various pharmaceutically acceptable positively charged ions.The example of these salt comprises the basic metal or the alkaline earth salt of The compounds of this invention, exactly is calcium salt, magnesium salts, sodium salt and sylvite.
Some The compounds of this invention can have asymmetric center, therefore exists with different mappings and diastereomeric form formula.The present invention relates to the purposes of all optically active isomers of The compounds of this invention and steric isomer and composition thereof, relate to all pharmaceutical compositions and the methods of treatment that can adopt or contain them.
The present invention includes such The compounds of this invention and pharmacy acceptable salt thereof, wherein one or more hydrogen, carbon or other atom are replaced by its isotropic substance.Such compound can be used as research and diagnostic tool in the metabolism pharmacokinetic studies with in conjunction with in measuring.
Preferred formula I compound comprises that wherein a is 1 and R
1Be (C
1-C
10) those of alkyl.
Other preferred formula I compound comprises wherein R
2Be those of hydrogen.
Other preferred formula I compound comprises wherein R
3Be N
3, R
10NH, R
10C (O), R
10NHC (O) NH or R
10Those of NHNHC (O) NH.
Other preferred formula I compound comprises wherein R
4Be hydrogen, R
14NH or R
14Those of S.
Other preferred formula I compound comprises wherein R
6Be those of ethyl.
Other preferred formula I compound comprises that wherein W is that C=O and Y are NR
17Those.
Preferred formula I compound comprises that wherein a is 1; R
1Be (C
1-C
10) alkyl; R
2Be hydrogen; R
3Be N
3, R
10NH, R
10C (O), R
10NHC (O) NH or R
10NHNHC (O) NH; R
4Be hydrogen, R
14NH or R
14S and R
6Be those of ethyl.
Preferred formula I compound comprises that wherein a is 1; R
1Be (C
1-C
10) alkyl; R
2Be hydrogen; R
3And R
4Form formula II compound with the carbon that they connected; W is that C=O and Y are NR
17Those.
Concrete preferred formula I compound comprises as follows:
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2,11-(imino-carbonyl (2-(3-(4-quinolyl) propyl group) hydrazono-))-3-oxo erythromycin;
11,12-dideoxy-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11,12-dideoxy-11,12-two dehydrogenations-3-takes off ((2, the 6-dideoxy-own ribose of 3-C-methyl-3-O-methyl-α-L-pyrans-5-yl) oxygen)-6-O-methyl isophthalic acid 0-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo-8-and show erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo-8-erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo-12,11-(imino-carbonyl hydrazono-) erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-imino-carbonyl hydrazono--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-isothiocyanato-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-alkynes propoxy--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate; With
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate.
The present invention also relates to be used for the pharmaceutical composition of Mammals, fish or birds treatment for diseases, these illnesss are selected from infectation of bacteria, protozoal infections or the illness relevant with infectation of bacteria or protozoal infections, and this pharmaceutical composition comprises formula I compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
The present invention also relates to treat the method for Mammals, fish or birds illness, these illnesss are selected from infectation of bacteria, protozoal infections or the illness relevant with infectation of bacteria or protozoal infections, and this method comprises the formula I compound of significant quantity on the therapeutics or its pharmacy acceptable salt described Mammals, fish or birds administration.
The present invention also relates to be used for Mammals, particularly people's cancer, the particularly pharmaceutical composition of nonsmall-cell lung cancer treatment, this pharmaceutical composition comprises formula I compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
The present invention also relates to treat the method for mammalian cancer, particularly nonsmall-cell lung cancer, this method comprises the formula I compound of significant quantity on the therapeutics or its pharmacy acceptable salt described Mammals administration.
Verb used herein " treatment " refers to reverse, alleviate, suppress the progress of illness that this term is suitable for or disease or prevents it unless otherwise specified, perhaps at one or more symptoms of this illness or disease.Noun used herein " treatment " refers to as the behavior of defined verb " treatment " just now.
Unless otherwise specified, term used herein or wording " infectation of bacteria ", " protozoal infections " comprise as follows with " illness relevant with infectation of bacteria or protozoal infections ": infect relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and mastoiditis with streptococcus pneumoniae, hemophilus influenzae, Moraxella catarrhalis, streptococcus aureus or peptostreptococcus; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis with streptococcus pyogenes, C family and G family suis, diphtheria clostridium (clostridiumdiptheriae) or Actinobacillus haemolyticum; The respiratory tract infection relevant with mycoplasma pneumoniae, legionella pneumophilia, streptococcus pneumoniae, hemophilus influenzae or infection involving chlamydia pneumoniae; With streptococcus aureus, coagulase-positive staphylococci (being staphylococcus epidermidis, staphylococcus haemolyticus etc.), streptococcus pyogenes, streptococcus agalactiae, suis C-F family (minute-colony streptococci), viridans streptococci (viridans streptococci), minimum coryneform bacteria (Corynebacterium minutissimum), clostridium or relevant non-concurrency skin and soft tissue infection, abscess and osteomyelitis and the lochiopyra of Bartonella henselae; Infect relevant uncomplicated acute urinary tract infection with Staphylococcus saprophyticus or faecalis; Urethritis and trachelitis; Infect relevant sexually transmitted disease (STD) with chlamydia trachomatis, Ducrey bacillus, Tyreponema pallidum, Ureaplasma urealyticum or Diplococcus gonorrhoeae; With streptococcus aureus (food poisoning and toxic shock syndrome) or A, the B toxin disease relevant with the streptococcal infection of C family; The ulcer relevant with helicobacter pylori infection; Infect relevant whole body heating syndrome with borrelia obermeieri; Infect relevant Lyme disease with Borrelia burgdofferi; Infect relevant conjunctivitis, keratitis and dacryocystitis with chlamydia trachomatis, Diplococcus gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, hemophilus influenzae or Listera spp; Infect relevant dissemination mycobacterium tuberculosis avium syndrome (MAC) with mycobacterium tuberculosis avium or Mycobacterium intracellulare; Infect relevant gastro-enteritis with campylobacter jejuni; Infect relevant intestinal protozoa disease with Cryptosporidium (Cryptosporidium spp.); Infect relevant odontogenic infection with viridans streptococci; Infect relevant persistence cough with bordetella pertussis; The gas gangrene relevant with clostridium perfringens or infection due to Bacteroides; With atherosclerosis or the cardiovascular disorder relevant with infection involving chlamydia pneumoniae.The animal bacterial infection that can be treated or prevent comprises and pasteurella hemolytica, pasteurella multocida, Mycoplasma bovis or the relevant ox respiratory disease of Bordetella spp with protozoal infections and the illness relevant with these infection; Infect relevant cow intestinal disease with bacillus coli or protozoon (being coccidia, Cryptosporidium etc.); Infect relevant dairy cow mastitis with streptococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, Klebsiella pneumoniae, corynebacterium or faecalis; The pig respiratory disease relevant with A.pleuro, pasteurella multocida or mycoplasma infection; Infect relevant chitling disease with the little snake bacterium of bacillus coli, Lawsonia intracellularis, salmonella or swine dysentery; The foot rot of cattle relevant with Fusobacterium spp; Infect relevant cow metritis with bacillus coli; Infect relevant cow hairy warts with actinomyces pseudonecrophorus or Bacteroides nodosus; Infect relevant cow pink-eye with hemophilus bovis; Infect relevant cow premature labor with protozoon (being neospora (neosporium)); Infect relevant dog and cat urinary tract infection with bacillus coli; Infect relevant dog and cat skin skin and soft tissue infection with staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative staphylococcus (coagulase neg.Staph.) or pasteurella multocida; With infect relevant dog and cat tooth or oral cavity infection with Alcaligenes, bacterioide, clostridium, enterobacteria, eubacterium, Peptostreptococcus, porphyromonas or prevotella.According to method of the present invention, other infectation of bacteria that can be treated or prevent infects relevant illness referring to the 26th edition (antimicrobial therapy company 1996) (" The Sanford Guide To Antimicrobial Therapy " such as J.P.Sanford " Sanford antimicrobial therapy guide " with protozoal infections and with these, 26thEdition, Antimicrobial Therapy, Inc., 1996).
The present invention also relates to following formula: compound
Or its pharmacy acceptable salt; Wherein the dotted line between 10 and 11 is represented optional double bond; A is 0 or 1; R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be N
3, R
10NH, R
10C (O) NH, R
10NHC (O) NH, R
10NHC (S) NH, R
10NHNHC (O) NH, R
10ONHC (O) NH or R
10OC (O) NH, R wherein
10Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl; Perhaps R
3Be R
14(C
2-C
4) alkynyl, R wherein
11Be (C
1-C
6) alkyl, (C
6-C
10) alkyl (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl; Perhaps R
3Be R
12R
13N, R wherein
12And R
13Be hydrogen, (C independently of one another
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl;
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement;
Its condition is if a is zero, then R
1Be hydrogen.
Wherein a is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl independently are selected from halogen, (C by one to three alternatively
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Substituting group replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be NH
2, N
3, O=C=N or S=C=N;
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement.
The present invention also relates to the following formula midbody compound
Wherein a is 0 or 1; R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be NH
2Or N
3
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement.
Wherein a is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement.
Detailed description of the invention
Following reaction process is set forth the preparation of The compounds of this invention.Unless otherwise specified, a, the R in reaction process and the subsequent discussion
1, R
2, R
3, R
4, R
5And R
6Define the same.
Preparation C
Flow process 1
Flow process 2
Flow process 5
Flow process 7
Flow process 8
Flow process 9
Flow process 11
In the reaction 1 of preparation A, formula VII compound is converted into corresponding formula VI ketene diacetal compound; R among the formula VII
22Be good leavings group, for example (C
1-C
6) alkane sulfonyloxy, (C
6-C
10) arylsulfonyloxy, (C
1-C
6) acyloxy or imidazoles ketonic oxygen base, method for transformation is in the presence of a kind of polar aprotic solvent, for example acetonitrile, dimethyl formamide, tetrahydrofuran (THF), be preferably acetonitrile, with a kind of alkaline purification of VII, for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, ethyl diisopropylamine, triethylamine, hexamethyl two silicon Lithium Azides or hexamethyl two silicon potassium azide are preferably 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.With reactant about 20 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, stir about was preferably about 2 hours to about 6 hours time phase in 0.5 hour.
In the reaction 2 of preparation A, formula VI ketene diacetal compound is converted into corresponding formula V trinitride, method be a kind of lewis acidic in the presence of, for example tin chloride (IV), titanium chloride (IV), boron trifluoride diethyl ether compound or aluminum chloride, be preferably tin chloride (IV), and in the presence of a kind of aprotonic solvent, make VI and a kind of azide agent reaction, for example azido-trimethyl silicane, sodiumazide or tributyl azide tin are preferably the azido-trimethyl silicane.The solvent that is fit to comprises methylene dichloride, ethylene dichloride, chloroform or tetracol phenixin, is preferably methylene dichloride.Be reflected at approximately-78 ℃ to about 25 ℃ temperature, be preferably about 0 ℃, carry out about 3 hours, be preferably about 6 hours to about 12 hours time phase.
In the reaction 3 of preparation A, formula V trinitride is converted into corresponding formula IV aminocompound, method is in the presence of hydrogen and a kind of catalyzer, for example palladium-carbon, palladium-lime carbonate, platinum oxide (IV) or ruthenium-carbon, be preferably palladium-lime carbonate, and in the presence of a kind of solvent, for example ethanol, methyl alcohol or ethyl acetate, be preferably ethanol, reduction V.Be reflected at about 1psi to the pressure of about 50psi, be preferably about 20psi,, be preferably about 25 ℃, carry out 1 hour extremely about 6 hours time phase, be preferably about 2.5 hours at about 0 ℃ extremely under about 50 ℃ temperature.
In the reaction 4 of preparation A, formula IV aminocompound is converted into corresponding formula XXII isocyanate compound, method is in the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF) Huo diox makes the reaction of IV and phosgene or triphosgene.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 0 ℃, carry out 0.5 hour to about 12 hours time phase, be preferably about 2 hours.
In the reaction 5 of preparation A, formula V compound is converted into corresponding formula IX compound, and method is in ethanol, tetrahydrofuran (THF) Huo diox, heating V to about 30 ℃ to about 100 ℃ temperature, be preferably about 70 ℃, carry out about 0.5 hour, be preferably about 2 hours to about 6 hours time phase.
In the reaction 6 of preparation A, formula IX trinitride is converted into corresponding formula VIII aminocompound, reacts 3 described steps and carries out according to above preparing A.
In the reaction 1 of preparation B, formula VIII aminocompound is converted into corresponding formula XIII isocyanate compound, reacts 4 described steps and carries out according to above preparing A.
In the reaction 1 of preparation C, formula VI ketene diacetal compound is converted into corresponding formula XXXIX compound, works as R
4By one or two nitro, R
14O
2During methylene radical that C or cyano group replace, method for transformation is in the presence of a kind of alkali, for example 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, triethylamine, sodium hydride or two (trimethyl silyl) lithium amide, be preferably 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), acetonitrile or dimethyl formamide, be preferably acetonitrile, make VI and formula R
4The reaction of H compound.Be reflected at approximately-20 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, carry out about 0.5 hour, be preferably about 2 hours to about 6 hours time phase.
In the reaction 1 of flow process 1, formula IV aminocompound is converted into corresponding formula X amide compound, and method is in the presence of a kind of alkali, and for example pyridine or triethylamine make IV and formula R
10The reaction of-CO-X compound, X wherein is chlorine, bromine or a kind of acid anhydrides.The solvent that is fit to comprises methylene dichloride, ethylene dichloride, tetrahydrofuran (THF) Huo diox, is preferably tetrahydrofuran (THF).With reactant about 0 ℃ to about 50 ℃ temperature, be preferably about 0 ℃, stir about was preferably about 12 hours to about 24 hours time phase in 1 hour.The reaction of production X compound acid amides also can be carried out like this, in the presence of a kind of dewatering agent, and for example 1,3-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide makes IV and formula R
10The reaction of-COOH carboxylic acid cpd.
In the reaction 2 of flow process 1, formula IV aminocompound is converted into corresponding formula XI carbamide compound, and method is in the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF) Huo diox makes the reaction of IV and phosgene or triphosgene.In the presence of tetrahydrofuran (THF), diox or dimethyl formamide, with formula R
10NH
2Amine join in the formed reaction mixture.Be reflected at about 0 ℃ to about 100 ℃ temperature, be preferably about 65 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 6 hours.The reaction of the urea of production XI compound also can be carried out like this, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), diox or dimethyl formamide make IV and formula R
10The reaction of N=C=O compound.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 12 hours.
In the reaction 3 of flow process 1, formula IV aminocompound is converted into corresponding formula XII carbamate compounds, and method is in the presence of a kind of alkali, for example triethylamine, pyridine or ethyl diisopropylamine, and in the presence of a kind of aprotonic solvent, make IV and formula R
10The reaction of COCl chloro-formic ester.The solvent that is fit to comprises tetrahydrofuran (THF), diox or dimethyl formamide.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 6 hours.Formula XII compound also can prepare like this, makes formula XXII compound and formula R
10The reaction of OH alcohol.
In the reaction 4 of flow process 1, formula IV aminocompound is converted into corresponding formula XIII compound, and method is in the presence of a kind of catalyzer, and for example palladium-carbon utilizes formula R
10CHO aldehydes or ketones and a kind of reductive agent, for example sodium cyanoborohydride, sodium triacetoxy borohydride or hydrogen carry out the reductive amination of IV.The solvent that is fit to comprises ethanol or methyl alcohol.With reaction mixture about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, stir about was preferably about 12 hours to about 24 hours time phase in 0.5 hour.
In the reaction 1 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XIV compound, method is in the presence of a kind of acid, for example tin chloride (IV), titanium chloride (IV), titanium isopropylate (IV) or boron trifluoride diethyl ether compound, and in the presence of a kind of aprotonic solvent, for example methylene dichloride and ethylene dichloride make VI and formula R
10The reaction of-OH alkylol cpd.Be reflected at approximately-78 ℃ to the temperature of room temperature, be preferably about 0 ℃, carry out about 1 hour, be preferably about 6 hours to about 24 hours time phase.
In the reaction 2 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XV compound, method is in the presence of a kind of acid, for example tin chloride (IV), titanium chloride (IV), titanium isopropylate (IV) or boron trifluoride diethyl ether compound, and in the presence of a kind of polar aprotic solvent, for example methylene dichloride makes VI and formula R
10The reaction of-SH mercaptan compound.Be reflected at approximately-78 ℃ to the temperature of room temperature, be preferably about 0 ℃, carry out about 1 hour, be preferably about 6 hours to about 24 hours time phase.
In the reaction 3 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XVI cyano compound, method is in the presence of a kind of acid, tin chloride (IV) for example, and in the presence of a kind of aprotonic solvent, for example methylene dichloride and ethylene dichloride make the reaction of VI and trimethyl silyl cyanogen or tetrabutyl ammonium cyanide.Be reflected at approximately-78 ℃ to the temperature of room temperature, be preferably about 0 ℃, carry out about 1 hour, be preferably about 6 hours to about 24 hours time phase.
In the reaction 4 of flow process 2, formula VI ketene diacetal compound is converted into corresponding formula XVII compound, method is in the presence of a kind of acid, tin chloride (IV) for example, and in the presence of a kind of aprotonic solvent, for example methylene dichloride, ethylene dichloride, tetrahydrofuran (THF) Huo diox make VI and trimethyl silyl lsothiocyanates react about 1 hour to about 24 hours time phase, are preferably about 6 hours.In the presence of tetrahydrofuran (THF), diox or dimethyl formamide, with formula R
10NH
2Amine join in the formed reaction mixture.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 6 hours.
In the reaction 1 of flow process 3, formula VIII aminocompound is converted into corresponding formula XVIII amide compound, carries out according to flow process 1 reaction 1 described step above.
In the reaction 2 of flow process 3, formula VIII aminocompound is converted into corresponding formula XIX carbamide compound, carries out according to flow process 1 reaction 2 described steps above.
In the reaction 3 of flow process 3, formula VIII aminocompound is converted into corresponding formula XX carbamate compounds, carries out according to flow process 1 reaction 3 described steps above.
In the reaction 4 of flow process 3, formula VIII aminocompound is converted into corresponding formula XXI compound, carries out according to flow process 1 reaction 4 described steps above.
In the reaction 1 of flow process 4, formula XXII isocyanate compound is converted into corresponding formula XXIII compound, and method is in the presence of a kind of aprotonic solvent, and for example tetrahydrofuran (THF), diox or dimethyl formamide make XXII and formula R
19ONH
2The compound reaction.Be reflected at about 0 ℃ to about 100 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 6 hours.
In the reaction 2 of flow process 4, formula XXIII compound is converted into corresponding formula XIV ring carbamide compound, method is to be with or without under the existence of potassium hydroxide, sodium hydroxide, potassium tert.-butoxide or acetate and a kind of solvent, and for example toluene, benzene or dimethyl formamide heat XXIII.Be reflected at about 25 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 3 hours.
In the reaction 1 of flow process 5, formula XI carbamide compound is converted into corresponding formula XXV ring carbamide compound, carries out according to flow process 4 reactions 2 described steps above.
In the reaction 1 of flow process 6, formula IV ketene diacetal compound is converted into corresponding formula XXVI isothiocyanic acid ester cpds, method be a kind of lewis acidic in the presence of, for example tin chloride (IV), titanium chloride (IV), boron trifluoride diethyl ether compound or aluminum chloride, be preferably tin chloride (IV), and in the presence of a kind of aprotonic solvent, make the reaction of IV and trimethyl silyl lsothiocyanates.The solvent that is fit to comprises methylene dichloride, ethylene dichloride, chloroform or tetracol phenixin, is preferably methylene dichloride.Be reflected at approximately-78 ℃ to about 50 ℃ temperature, be preferably about 0 ℃, carry out about 0.5 hour, be preferably about 12 hours to about 24 hours time phase.
In the reaction 2 of flow process 6, formula XXVI isothiocyanic acid ester is converted into corresponding formula XXVII thiourea compound, carries out according to flow process 1 reaction 2 described steps above.
In the reaction 3 of flow process 6, formula XXVII thiourea compound is converted into corresponding formula XXVIII aminothiazole quinoline compound, carries out according to flow process 4 reactions 2 described steps above.
In the reaction 1 of flow process 7, formula XXIX ring carbamide compound is converted into corresponding formula XXX compound, and method is in the presence of ethanol or pyridine, makes XXIX and formula NHOR
16The compound reaction.Be reflected at about 25 ℃ to about 100 ℃ temperature, be preferably about 80 ℃, carry out about 1 hour to about 48 hours time phase, be preferably about 24 hours.
In the reaction 2 of flow process 7, formula XXX compound is converted into corresponding formula XXXI compound, and method is in the presence of sodium borohydride and a kind of polar aprotic solvent, and for example methyl alcohol or ethanol are preferably methyl alcohol, make XXX and formula R
19The reaction of CHO aldehyde cpd.Be reflected at about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 12 hours.
In the reaction 1 of flow process 8, formula XXXII aminocompound is converted into corresponding formula XXXIII compound, method is in the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), diox or methylene dichloride make XXXII and sulphonyl diimidazole, SULPHURYL CHLORIDE or thionyl chloride reaction.Be reflected at approximately-78 ℃ to about 25 ℃ temperature, be preferably about 0 ℃, carry out about 0.5 hour, be preferably about 12 hours to about 24 hours time phase.In the presence of a kind of alkali, for example triethylamine or pyridine, and in the presence of a kind of aprotonic solvent, for example tetrahydrofuran (THF), diox or methylene dichloride are with formula R
17NH
2Amine join in the formed reaction mixture.Be reflected at about 0 ℃ to about 25 ℃ temperature, be preferably about 0 ℃, carry out about 0.5 hour to about 24 hours time phase, be preferably about 6 hours.
In the reaction 2 of flow process 8, formula XXXIII compound is converted into corresponding formula XXXIV compound, method be with or without potassium tert.-butoxide or acetate in the presence of, in tetrahydrofuran (THF) or dimethyl formamide, heat XXXIII.Be reflected at about 60 ℃ to about 100 ℃ temperature, be preferably about 85 ℃, carry out about 0.5 hour to about 12 hours time phase, be preferably about 2 hours.
In the reaction 1 of flow process 9, formula XIII compound is converted into corresponding formula XXXV compound, carries out according to flow process 4 reactions 1 described step above.
In the reaction 2 of flow process 9, formula XXXV compound is converted into corresponding formula XXXVII compound, and method is to make XXXV and formula R
10CHO aldehyde and the reaction of a kind of reductive agent, for example sodium cyanoborohydride.The solvent that is fit to comprises methyl alcohol, ethanol or ethylene dichloride.With reaction mixture about 0 ℃ to about 50 ℃ temperature, be preferably about 25 ℃, stir about was preferably about 12 hours to about 24 hours time phase in 0.5 hour.
In the reaction 1 of flow process 10, formula XIII isocyanate compound is converted into corresponding formula XXXVI compound, carries out according to flow process 4 reactions 1 described step above.
In the reaction 1 of flow process 11, formula XXVII thiourea compound is converted into corresponding formula XXXVIII cyclic thiourea compound, carries out according to flow process 4 reactions 2 described steps above.
In the reaction 1 of flow process 12, formula XXIX compound is converted into corresponding formula XXXX compound, carries out according to flow process 9 reactions 2 described steps above.
Formula VII initial compounds can be according to United States Patent (USP) 5543400 described method preparations.R wherein
1Be that not isoplastic formula VII initial compounds can be according to WO 98/09978 described method preparation.
The The compounds of this invention of alkalescence can form multiple different salt with various inorganic and organic acids.Although these salt must be pharmaceutically acceptable to animals administer, but also often need the initial pharmaceutically unacceptable salt that from reaction mixture, separates The compounds of this invention in practice, processing by alkaline reagents then, simply the latter is converted into the free alkali cpd, subsequently latter's free alkali is converted into pharmaceutically-acceptable acid addition.The acid salt of alkali cpd of the present invention is easy to prepare, and method is in a kind of water-containing solvent medium or suitable organic solvent, and for example methyl alcohol or ethanol are handled this alkali cpd with being essentially normal selected inorganic or organic acid.Evaporating solvent is easy to obtain required solid salt carefully.Required hydrochlorate also can be precipitated out from the solution of free alkali organic solvent, and method is to add suitable inorganic or organic acid in this solution.
The tart The compounds of this invention can form alkali salt with various pharmaceutically acceptable positively charged ions.The example of these salt comprises the salt of basic metal or alkaline-earth metal, definitely is sodium salt and sylvite.These salt all prepare by common process.The chemical bases that is used to prepare pharmaceutically acceptable alkali salt of the present invention as reagent is to form those of nontoxic alkali salt with acidic cpd of the present invention.Nontoxic alkali salt like this comprise from pharmaceutically acceptable positively charged ion deutero-those, for example sodium, potassium, calcium and magnesium etc.These salt can be easy to preparation, and method is that corresponding acidic cpd is handled with containing the required pharmaceutically acceptable cationic aqueous solution, evaporates gained solution then to doing, preferably under reduced pressure.Perhaps, they also can prepare like this, the low-grade alkane alcohol solution and the required alkali metal alcoholate of acidic cpd is mixed together, then by aforementioned same way as evaporation gained solution to doing.In two kinds of methods, preferably adopt the reagent of stoichiometric quantity, purpose be guarantee to react completely and the yield of required end product the highest.
The compounds of this invention is proved by the ability that this compound suppresses defined human pathogen (measuring I) or animal pathogen (measuring II and III) strain growth the activity of antibacterium and protozoon pathogenic agent.
Measure I
Following mensuration I adopts ordinary method and criteria for interpretation, through design, can provide the direction of chemically modified, and this chemically modified can make compound evade clear and definite macrolide resistance mechanism.Measure among the I, collect one group of bacterial isolates, comprise all types of target cause of disease kind, comprising by the representative of the macrolide resistance mechanism of characterized.Use of this group bacterial strain can be set up chemical structure/activity relationship, measures effectiveness, activity profile and structural element or may be necessary modification to getting rid of resistance mechanism.The bacterial pathogens that comprises the screening group is listed in the following table.As a rule, macrolide susceptibility parent bacterial strain and all be utilizable from its deutero-macrocyclic lactone bacterial strain is to provide the estimating more accurately of ability of evading resistance mechanism about compound.The bacterial strain tolerance macrolide, lincosamides and the Streptogramin B microbiotic that contain the gene of ermA/ermB/ermC by name, this is owing to the modification (methylate) of Erm methylase to the 23SrRNA molecule, thereby has generally prevented the combination of whole three kinds of structure types.Described in two types macrolide effluent: the msrA coding staphylococcus effluent system and prevented the component that macrolide and streptogramin enter, and as if the mefA/E coding only flow out the transmembrane protein of macrolide.The inactivation of macrolide antibiotic may take place, and the cracking (esterase) of phosphorylation of 2 '-hydroxyl (mph) or macrolide can both mediate this deactivation.Utilize conventional polymerase chain reaction (PCR) technology and/or, can carry out characterized bacterial strain by the order-checking of resistance determiner.Round pcr application in this application is referring to " PCR is to the detection of erythromycin resistance determiner " " biocide and chemotherapy " such as J.Sutcliffe (" Detection Of Erythromycin-Resistant DeterminantsBy PCR ", Antimicrobial Agents and Chemotherapy) 40 (11), 2562-2566 (1996).Be determined in the microtiter plates and carry out, explain with reference to PerformanceStandards for Antimicrobial Disk Susceptibility Tests-Sixth Edition; Approved Standard is published by guidance group of standard committee of national clinical labororatory (NCCLS); Relatively to the minimum inhibitory concentration (MIC) of bacterial strain.At first compound is dissolved in dimethyl sulfoxide (DMSO) (DMSO), as the 40mg/ml stock solution.
Strain name | Macrocyclic lactone mechanism |
Streptococcus aureus 1116 | The susceptibility parent |
Streptococcus aureus 1117 | ????ermB |
Streptococcus aureus 0052 | The susceptibility parent |
Streptococcus aureus 1120 | ????ermC |
Streptococcus aureus 1032 | MsrA, mph, esterase |
Staphylococcus haemolyticus 1006 | ????msrA、mph |
Streptococcus pyogenes 0203 | The susceptibility parent |
Streptococcus pyogenes 1079 | ????ermB |
Streptococcus pyogenes 1062 | The susceptibility parent |
Streptococcus pyogenes 1061 | ????ermB |
Streptococcus pyogenes 1064 | ????ermB |
Streptococcus agalactiae 1024 | The susceptibility parent |
Streptococcus agalactiae 1023 | ????ermB |
Streptococcus pneumoniae 1016 | Susceptibility |
Streptococcus pneumoniae 1046 | ????ermB |
Streptococcus pneumoniae 1095 | ????ermB |
Streptococcus pneumoniae 1175 | ????mefE |
Streptococcus pneumoniae 0085 | Susceptibility |
Hemophilus influenzae 0131 | Susceptibility |
Moraxella catarrhalis 0040 | Susceptibility |
Moraxella catarrhalis 1055 | The medium tolerance of erythromycin |
Bacillus coli 0266 | Susceptibility |
Measure the activity that II is used to test the antagonism pasteurella multocida, measure the activity that III is used to test the antagonism pasteurella hemolytica.
Measure II
The basis of this mensuration is the liquid diluting method of microlitre form (format).With the single colony inoculation of pasteurella multocida (59A067 bacterial strain) in 5ml brain heart infusion (BHI) meat soup.Test compound is such preliminary, and the 1mg compound is dissolved in 125 μ l dimethyl sulfoxide (DMSO) (DMSO).Utilize nonvaccinated BHI meat soup to prepare the diluent of test compound.The concentration range of used test compound gets by the twice serial dilution from 200 μ g/ml to 0.098 μ g/ml.BHI through the pasteurella multocida inoculation dilutes with nonvaccinated BHI meat soup, obtains 10
4The per 200 μ l of individual cell suspension.The BHI cell suspension is mixed with the various serial dilutions of test compound, cultivated 18 hours down at 37 ℃.Concentration when minimum inhibitory concentration (MIC) equals compound the growth of pasteurella multocida is showed 100% restraining effect, this measures by comparing with nonvaccinated contrast.
Measure III
The basis of this mensuration is the agar dilution that utilizes Steers Replicator to be carried out.Separate two to five bacterium colonies from agar plate, be seeded among the BHI,, shake it (200rpm) simultaneously 37 ℃ of following overnight incubation.The next morning, the pre-culture of pasteurella hemolytica that 300 μ l are fully grown is seeded in the fresh BHI meat soup of 3ml, cultivates down at 37 ℃, shakes it (200rpm) simultaneously.An amount of test compound is dissolved in ethanol, prepares a series of twice serial dilutions.The BHI agar of the various serial dilutions of 2ml with the 18ml fusing is mixed, solidify.When the pasteurella hemolytica culture of being inoculated reaches the 0.5McFarland standard density, utilize Steers Replicator that about 5 μ l pasteurella hemolytica cultures are seeded on the BHI agar plate that contains various concentration test compounds, cultivated 18 hours down at 37 ℃.The initial concentration scope of test compound is 100-200 μ g/ml.Concentration when MIC equals test compound the growth of pasteurella hemolytica is showed 100% restraining effect, this measures by comparing with nonvaccinated contrast.
The activity in vivo of formula I compound can be measured by the protection of animal research of routine, and these researchs are well known to those skilled in the art, carry out in mouse usually.
According to the arrival order mouse is distributed in (10 in every cage) in the cage, minimum 48 hours adaptation time is arranged before the use.Animal intraperitoneal inoculation 0.5ml 3 * 10
3CFU/ml bacterial suspension (pasteurella multocida 59A006 bacterial strain).Each experiment has at least 3 non-administration control groups, comprises one group with the infection of 0.1X challenge dose, uses the 1X challenge dose to infect for two groups; Also can adopt the 10X attack bacteria to infect data set.Usually, all mouse in a given research all in 30-90 minute by infectation of bacteria, especially using repeatedly syringe (for example Cornwall syringe) to carry out under the situation of infectation of bacteria.Infectation of bacteria began back 30 minutes, carried out the compounds for treating first time.If all animals all by infectation of bacteria, may need second people to begin compound administration when finishing in 30 minutes.Route of administration is subcutaneous or oral.The subcutaneous administration position is at the lax skin of neck dorsal part, and oral administration is undertaken by the syringe needle of feeding.In both cases, the medication volume of every mouse is 0.2ml.30 minutes, 4 hours and 24 hours are with compound administration behind infectation of bacteria.The control compound of known effect is also included within each test by identical administration.Observe animal every day, write down every group survival quantity.Proceed 96 hours (four days) of pasteurella multocida model monitoring behind the aggressive infectation of bacteria.
Calculate PD
50, under this dosage, the compound of being tested is protected the 50% dead because of infectation of bacteria of one group of mouse, is not having under the situation of pharmacological agent, and this infectation of bacteria will be fatefulue.
Formula I compound and pharmacy acceptable salt thereof (hereinafter referred to as " active compound ") can be used for the treatment or the prevention of bacterium or protozoal infections by oral, parenteral, part or rectum administration.In general, the most desirable dosage scope of these compounds from the every kg body weight of about 0.2mg every day (mg/kg/ days) to about 200mg/kg/ days, divide single or multiple administration (being administration every day 1 to 4 time), but, also can carry out necessary adjustment according to curee's kind, body weight and condition and selected specific administration approach.But, the most preferably adopt about 4mg/kg/ days to about 50mg/kg/ days dosage level.Nonetheless, according to the kinds of the Mammals of being treated, fish or birds and to the reaction and the selected types of drug preparations of described medicine and carry out the time of administration stage with at interval, can also adjust.In some cases, the dosage level that is lower than above-mentioned scope lower limit may be more suitable, and in other cases, can adopt bigger dosage, and can not cause any deleterious side effect, as long as earlier this heavy dose is divided into some low doses, administration gets final product in whole day.
Active compound can combine administration separately or with pharmaceutically acceptable carrier or thinner, route of administration as mentioned above, and administration can divide single agent or multi-agent to carry out.Or rather, active compound can be with multiple different formulation administration, that is to say that they can be combined into tablet, capsule, lozenge, dragee, hard candy agent, powder agent, sprays, creme, salve, suppository, jelly, gelifying agent, paste, lotion, ointment, aqueous suspensions, injection solution, elixir, syrup etc. with various pharmaceutically acceptable inert supports.Such carrier comprises solid diluent or weighting agent, sterile aqueous media and various nontoxic organic solvents etc.And combination of oral medication can suitably be given sweet taste and/or flavoring.In general, the concentration level scope of active compound in these formulations is from about 5.0 weight % to about 70 weight %.
About oral administration, can adopt tablet, wherein contain various vehicle, for example Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and glycine, with various disintegrating agents, for example starch (being preferably corn, potato or tapioca (flour)), alginic acid and some composition silicate, and Granulating Bonding Agent, for example polyvinylpyrrolidone, sucrose, gelatin and gum arabic.In addition, for the purpose of compressing tablet, lubricant also is very useful, for example Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum.The solids composition that can also adopt similar type is as the weighting agent in the capsule; Preferred in this respect material also comprises lactose or toffee and macromolecule polyethylene glycol.When oral administration needs aqueous suspensions and/or elixir, active compound can combine with various sweeting agents or correctives, coloring material or stain, if necessary, also has emulsifying agent and/or suspension agent, and thinner, for example water, ethanol, propylene glycol, glycerine and various combination thereof.
About administered parenterally, can adopt the solution of active compound in sesame oil or peanut oil or aqueous propylene glycol.If necessary, the aqueous solution should suitably be cushioned (preferably pH is greater than 8), and at first gives liquid diluent with isotonicity.These aqueous solution are suitable for the purpose of intravenous injection.Oil solution is suitable for intra-arterial, intramuscular and hypodermic purpose.According to standard pharmaceutical technology well known by persons skilled in the art, be easy to realize the preparation of all these solution under aseptic condition.
In addition, also may be with active compound topical of the present invention, according to the standard pharmaceutical practice, this can be undertaken by creme, jelly, gelifying agent, paste, patch, ointment etc.
About to the animals administer except that the people, for example ox or domestic animal, active compound can be in animal-feed administration or as the administration of drencs composition oral.
Active compound also can be with the form administration of liposome release system, and for example monolayer vesicle, large unilamellar vesicles and multilayer are steeped.Liposome can generate from various phosphatide, for example cholesterol, stearylamine or phosphatidylcholine.
Active compound also can with soluble polymer coupling, for example orientable pharmaceutical carrier.Such polymkeric substance can comprise polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl MAAm phenyl, poly-hydroxyethyl asparagine-phenol or the polyoxyethylene-polylysine that is replaced by the palmityl residue.In addition, active compound can with a class Biodegradable polymeric coupling, can be used for realizing that controlled delivery of pharmaceutical agents discharges, for example the multipolymer of poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid, poly epsilon caprolactone lactone, polyhydroxybutyrate, poe, polyacetal, gather dihydropyrane, polybutylcyanoacrylate and crosslinked or amphipathic hydrogel segmented copolymer.
The following example is set forth the embodiment of invention, but the present invention is not limited to the scope of the concrete illustration of embodiment.
Embodiment 1
(a is 1 to formula XIII; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α or β; R
4It is the nitro methyl; R
6Be ethyl)
With 1, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (76 μ l, (a is 1 0.5mmol) to join formula VII; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
3It is the imidazoles carbonyl; R
4Be hydrogen; R
6Be ethyl) (71mg, 0.1mmol) (76 μ l are in 2ml acetonitrile solution 0.5mmol) with Nitromethane 99Min..
Gained solution refluxed 1.5 hours under nitrogen.(10ml) joins in the reaction mixture with ethyl acetate, and organic layer washs with saturated sodium dihydrogen phosphate.
Ethyl acetate solution salt water washing is through Na
2SO
4Dry.The gained resistates is through silica gel chromatography (TLC, 5%MeOH-0.5%NH behind the evaporating solvent
4OH-CH
2Cl
2) obtain 19mg (29%) title compound (the C-8 methyl is α); MS m/e 655 (M+1) and 11mg (17%) title compound (the C-8 methyl is β); MS m/e 655 (M+1)
Embodiment 2
(a is 1 to formula VI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α or β; R
6Be ethyl)
With 1, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (90 μ l, (a is 1 0.61mmol) to join formula VII; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
3It is the imidazoles carbonyl; R
4Be hydrogen; R
6Be ethyl) (4.30g is in 120ml anhydrous acetonitrile 6.1mmol).
Solution refluxed 4 hours.Evaporating solvent, resistates obtains 2.44g (67%) title compound (the C-8 methyl is α) and 643mg (18%) title compound (the C-8 methyl is β) through silica gel chromatography (1% methyl alcohol-0.5% triethylamine-methyl tertiary butyl ether); MS m/e 594 (M+1)
Embodiment 3
(a is 1 to formula V; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6Be ethyl)
(a is 1 with formula VI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6Be ethyl) (555mg, 0.94mmol) compound is dissolved in 40ml ethene, is cooled to-78 ℃.Drip trimethyl silyl trinitride (dichloromethane solutions of 744 μ l 1M tin chlorides (IV)).Reaction mixture slowly is warmed to room temperature, and stirring is spent the night.Add saturated sodium bicarbonate solution and make the reaction all standing, the product dichloromethane extraction.Dichloromethane layer salt water washing is through dried over sodium sulfate.Evaporating solvent, resistates obtains 410mg (69%) title compound through chromatogram; MS m/e 637 (M+1)
Embodiment 4
(a is 1 to formula X; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be methyl) and formula XVIII (a is 1; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be methyl)
Lin Dele (Lindlar) catalyzer (25mg) is joined formula V, and (a is 1; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6Being ethyl) (25mg, in 5ml ethanolic soln 0.039mmol), gained solution is used 20psi hydrogen hydrogenation at room temperature 2 hours to compound in the Parr wobbler.Solution is by diatomite filtration, evaporating solvent.Resistates is dissolved in the 2ml tetrahydrofuran (THF), handles down at 4 ℃ with 50 μ l pyridines and 50 μ l diacetyl oxides and spend the night.Evaporating solvent and excess reagent, resistates is by silica-gel plate chromatogram (5% methyl alcohol-0.5%NH
4OH-CH
2Cl
2) obtain 6.6mg (26%) formula X; MS m/e 653 (M+1) and 2.7mg (11%) formula XVIII; MSm/e 653 (M+1)
Embodiment 5
(a is 1 to formula XXIX; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
5It is Alpha-Methyl; R
6Be ethyl) and formula XXXV (a is 1; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6Be ethyl)
Lindlar catalyst (137mg) is joined formula V, and (a is 1; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6Being ethyl) (137mg is in 15ml ethanolic soln 0.215mmol) for compound.The hydrogenation 2 hours under 20psi hydrogen of gained solution.Solution under reduced pressure removes and desolvates by diatomite filtration.Resistates is dissolved in the 5ml tetrahydrofuran (THF), in ice bath, cools off.Add triethylamine (85 μ l, 0.611mmol, 2.84eq) photoreactive gas (0.25ml 1.93M toluene solution, 0.483mmol, 2.24eq).Solution stirred 2 hours down at 0 ℃.Reaction mixture is with the dilution of 25ml ethyl acetate, with saturated sodium bicarbonate solution and salt water washing.
After dried over sodium sulfate, under reduced pressure remove and desolvate.Then resistates is dissolved in the 2ml dimethyl formamide, and the adding anhydrous hydrazine (67 μ l, 2.15mmol, 10eq).Gained solution heated 6 hours down at 60 ℃.Under reduced pressure remove dimethyl formamide, resistates is through SiO
2Chromatogram (5% methyl alcohol-0.5%NH
4OH-CH
2Cl
2) obtain two kinds of integral part.SiO further passes through in first part
2Plate chromatography (7.5%MeOH-0.75%NH
4OH-CH
2Cl
2) obtain 9mg (7%) formula XXIX; MS m/e 627 (M+1)
Second section further passes through SiO
2Plate chromatography (5%MeOH-5% triethylamine-methyl tertiary butyl ether) obtains 12mg (9%) formula XXXV; MS m/e 627 (M+1)
Embodiment 6
(a is 1 to formula L; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
5It is Alpha-Methyl; R
6Be ethyl)
(a is 1 with formula XXIX; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
5It is methyl; R
6Being ethyl) (12m, 0.027mmol) (10mg 0.054mmol) is heated to 90 ℃ and reaches 14 hours compound in 1ml toluene with 3-(quinolyl-4) propionic aldehyde.Under reduced pressure remove toluene, resistates is dissolved in 1ml methyl alcohol (MeOH).Add sodium cyanoborohydride (16.9mg, 0.27mol) and acetate (25 μ l, 0.43mmol), gained solution at room temperature stirred 46 hours.Remove and desolvate, resistates is dissolved in methylene dichloride, with saturated sodium bicarbonate solution and salt water washing.After dried over sodium sulfate, evaporating solvent, resistates is through silica gel chromatography (TLC, 5% methyl alcohol-0.5%NH
4The OH-methylene dichloride) obtains the light yellow glassy mass of 13mg.This material further passes through silica gel chromatography (TLC, 5%MeOH-5% triethylamine-methyl tertiary butyl ether) and obtains 10mg (47%) title compound; MS m/e 839 (M+1)
Embodiment 7
(a is 1 to formula XI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl) and formula XIX (a is 1; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl)
Lindlar catalyst (137mg) is joined formula V, and (a is 1; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6Being ethyl) (137mg is in 15ml ethanolic soln 0.215mmol) for compound.The hydrogenation 2 hours under 20psi hydrogen of gained solution.Solution under reduced pressure removes and desolvates by diatomite filtration.Resistates is dissolved in 5ml THF, in ice bath, cools off.Add triethylamine (85 μ l, 0.611mmol, 2.84eq) toluene solution of photoreactive gas (250 μ l 1.93M solution, 0.483mmol, 2.24eq).Solution stirred 2 hours down at 0 ℃.Reaction mixture is used saturated NaHCO with the dilution of 25ml ethyl acetate
3Solution and salt water washing.Through Na
2SO
4Drying is under reduced pressure removed and is desolvated.Resistates is dissolved in 2ml DMF, and adding 4-(3-pyridyl)-1H-imidazoles-1-butylamine (139mg, 0.645mmol).
Solution is warmed to 60 ℃ and reaches 6 hours.Under reduced pressure remove DMF, resistates is through silica gel chromatography (TLC, 5%MeOH-0.5% NH
4OH-CH
2Cl
2) obtain two parts.The low-pole part is further passed through preparation type SiO
2TLC chromatogram (7.5%MeOH-0.75% NH
4OH-CH
2Cl
2) obtain 5mg (3%) formula XI compound; MS m/e 853 (M+1)
Strong polarity part is further passed through silica gel chromatography (TLC 5% MeOH-5% triethylamine-methyl tertiary butyl ether) and is obtained 12mg (7%) formula XIX compound; MS m/e 853 (M+1)
Embodiment 7B
(a is 1 to formula XXV; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl)
(a is 1 with XI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl) (35mg, 0.041mmol) the 1ml toluene solution with 3.5mg potassium hydroxide heated 1 hour down at 90 ℃.Cooled solution is diluted with ethyl acetate, washes with water.The waterbearing stratum is with fresh ethyl acetate extraction.Organic layer after the merging is through Na
2SO
4Drying, evaporation.Resistates is through silica gel chromatography (TLC 10%MeOH-CH
2Cl
2) obtain 15mg (43%) title compound; MS m/e 853
Embodiment 8
(a is 1 to formula XI; R
1It is methyl; R
2Be hydrogen; The C-8 methyl is α; R
6It is ethyl; R
7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl)
(a is 1 with formula XI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be 4-(3-pyridyl)-1H-imidazoles-1-butyl) compound (6mg, 7mmol) in methyl alcohol warm 1 hour.Evaporate methyl alcohol then, resistates is through silica gel chromatography (TLC 10%MeOH-1%NH
4OH-CH
2Cl
2) obtain 4mg (70%) title compound; MS m/e 812 (M+1)
Embodiment 9
(a is 1 to formula XXVI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α or β; R
5It is methyl; R
6Be ethyl)
(a is 1 with formula VI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α or β; R
6Be ethyl) (54mg 0.091mmol) is dissolved in 5ml CH
2Cl
2, cooling in dry ice-propanone is bathed.(128 μ l, 0.91mmol) and tin chloride (IV) solution (137 μ l 1M dichloromethane solution), gained solution is warmed to ambient temperature overnight gradually to add the trimethyl silyl lsothiocyanates.Add saturated sodium bicarbonate solution then, the product ethyl acetate extraction.Organic layer salt water washing is through dried over sodium sulfate.The gained resistates is through silica gel chromatography (hexane: acetone=2: 1) obtain 10mg (17%) title compound behind the evaporating solvent; MS m/e 653
Embodiment 10
(a is 1 to formula XIV; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α; R
6It is ethyl; R
7Be propargyl)
(a is 1 with formula VI; R
1It is methyl; R
2It is ethanoyl; The C-8 methyl is α or β; R
6Being ethyl) (118mg 0.2mmol) is dissolved in the 10ml anhydrous methylene chloride to compound, is cooled to-78 ℃.Add propargyl alcohol (35 μ l, 0.6mmol) and the dichloromethane solution of 1M tin chloride (IV) (220 μ l, 0.22mmol), solution is warmed to ambient temperature overnight gradually.Add saturated sodium bicarbonate solution and make the reaction all standing, dichloromethane solution salt water washing is through dried over sodium sulfate.The gained resistates is through silica gel chromatography (TLC 5% methyl alcohol-2.5% triethylamine-methyl tertiary butyl ether) behind the evaporation methylene dichloride.Suitable band passes through chromatogram (10% acetone-hexane) once more and obtains 6mg (5%) title compound with 5% methyl alcohol-dichloromethane extraction; MS m/e 649 (M+1)
Claims (24)
Or its pharmacy acceptable salt; Wherein
Dotted line between 10 and 11 is represented optional double bond;
A is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be amino, cyano group, N
3, R
10NH, R
10C (O) NH, R
10NHC (O) NH, R
10NHC (S) NH, R
10NHNHC (O) NH, R
10ONHC (O) NH, R
10O, R
10OC (O) NH, R
10S (O)
n, R
10Phosphinylidyne amino, R
10Sulfonamido, SH, R
10S, n definition wherein is the same, R
10Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl; Perhaps R
3Be R
12R
13N, R wherein
12And R
13Be hydrogen, (C independently of one another
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl;
R
4Be hydrogen, optional by one or two nitro, cyano group, R
14C (O) and R
14The methyl that OC (O) replaces; Perhaps R
4Be N
3, R
14O, R
14NH, R
14S, R wherein
14Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl; Perhaps R
4Be R
15N (C
1-C
6) alkyl, R wherein
15Be hydrogen, (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl;
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
Wherein the dotted line between nitrogen in formula II and the variable group W is represented optional double bond;
W is C=O, C=S, SO
2Or C=NR
10, R wherein
10Define the same;
Y is oxygen, sulphur or NR
17, R wherein
17Be hydrogen, R
19, R
19O or R
19NH, R wherein
19Be hydrogen, (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
5-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
18Be hydrogen, (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, aryl wherein and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
20R
21N, R
20C (O), R
20C (O) O, R
20OC (O), R
20C (O) NH, R
20NHC (O), R
20R
21NC (O) and R
20OC (O)
2, R wherein
20And R
21Be hydrogen, optional quilt (C independently of one another
6-C
10) acyl group or (C
5-C
10) (the C that replaces of aryl
1-C
6) alkyl or (C
2-C
9) heteroaryl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement;
Its condition is R
17Or R
18Have at least one to be hydrogen;
If its condition is dotted line representative two key, then R between 10 and 11
4Be hydrogen;
Its condition is if a is zero, then R
1Be hydrogen.
2, according to the compound of claim 1, wherein a is 1 and R
1Be (C
1-C
10) alkyl.
3, according to the compound of claim 1, R wherein
2Be hydrogen.
4, according to the compound of claim 1, R wherein
3Be N
3, R
10NH, R
10C (O) NH, R
10NHC (O) NH or R
10NHNHC (O) NH.
5, according to the compound of claim 1, R wherein
4Be hydrogen, R
14NH or R
14S.
6, according to the compound of claim 1, R wherein
6It is ethyl.
7, according to the compound of claim 1, wherein W is that C=O and Y are NR
17
8, according to the compound of claim 1, wherein a is 1; R
1Be (C
1-C
10) alkyl; R
2Be hydrogen; R
3Be N
3, R
10NH, R
10C (O), R
10NHC (O) NH or R
10NHNHC (O) NH; R
4Be hydrogen, R
14NH or R
14S and R
6It is ethyl.
9, according to the compound of claim 1, wherein a is 1; R
1Be (C
1-C
10) alkyl; R
2Be hydrogen; R
3And R
4Form formula II compound with the carbon that they connected; W is that C=O and Y are NR
17
10, according to the compound of claim 1, wherein said compound is selected from:
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2,11-(imino-carbonyl (2-(3-(4-quinolyl) propyl group) hydrazono-))-3-oxo erythromycin;
11,12-dideoxy-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 2-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11,12-dideoxy-11,12-two dehydrogenations-3-takes off ((2, the 6-dideoxy-own ribose of 3-C-methyl-3-O-methyl-α-L-pyrans-5-yl) oxygen)-6-O-methyl isophthalic acid 0-imino-carbonyl ((4-(4-(3-pyridyl)-1H-imidazoles-1-yl) butyl imino-))-3-oxo erythromycin;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-azido--6-O-methyl-3-oxo-8-and show erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-beta-amino-6-O-methyl-3-oxo-8-erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-pyrans is ribosyl) oxygen)-12-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-azido--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-beta-amino-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-acetylaminohydroxyphenylarsonic acid 6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl-3-oxo-12,11-(imino-carbonyl hydrazono-) erythromycin-2 '-acetate;
11,12-dideoxy-11,12-dehydrogenation-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-10-β-imino-carbonyl hydrazono--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11,12-dideoxy-10,11-two dehydrogenations-3-take off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-isothiocyanato-6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-12-β-alkynes propoxy--6-O-methyl-3-oxo erythromycin-2 '-acetate;
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate; With
11-deoxidation-10,11-two dehydrogenations-3-takes off ((2, the 6-dideoxy-3-C-methyl-3-O-methyl-α-own ribosyl of L-pyrans) oxygen)-6-O-methyl isophthalic acid 1-nitro methyl-8-table-3-oxo erythromycin-1,2-enol-1,12-cyclic ethers-2 '-acetate.
11, the pharmaceutical composition that is used for Mammals, fish or birds treatment for diseases, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this pharmaceutical composition comprises claim 1 compound and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
12, the pharmaceutical composition of claim 11, wherein said illness are to infect relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and mastoiditis with streptococcus pneumoniae, hemophilus influenzae, Moraxella catarrhalis, streptococcus aureus or peptostreptococcus; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis with streptococcus pyogenes, C family and G family suis, diphtheria clostridium or Actinobacillus haemolyticum; The respiratory tract infection relevant with mycoplasma pneumoniae, legionella pneumophilia, streptococcus pneumoniae, hemophilus influenzae or infection involving chlamydia pneumoniae; With streptococcus aureus, coagulase-positive staphylococci (being staphylococcus epidermidis, staphylococcus haemolyticus etc.), streptococcus pyogenes, streptococcus agalactiae, suis C-F family (minute-colony streptococci), viridans streptococci, minimum coryneform bacteria, clostridium or relevant non-concurrency skin and soft tissue infection, abscess and osteomyelitis and the lochiopyra of Bartonella henselae; Infect relevant uncomplicated acute urinary tract infection with Staphylococcus saprophyticus or faecalis; Urethritis and trachelitis; Infect relevant sexually transmitted disease (STD) with chlamydia trachomatis, Ducrey bacillus, Tyreponema pallidum, Ureaplasma urealyticum or Diplococcus gonorrhoeae; With streptococcus aureus (food poisoning and toxic shock syndrome) or A, the B toxin disease relevant with the streptococcal infection of C family; The ulcer relevant with helicobacter pylori infection; Infect relevant whole body heating syndrome with borrelia obermeieri; Infect relevant Lyme disease with Borrelia burgdofferi; Infect relevant conjunctivitis, keratitis and dacryocystitis with chlamydia trachomatis, Diplococcus gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, hemophilus influenzae or Listera spp; Infect relevant dissemination mycobacterium tuberculosis avium syndrome (MAC) disease with mycobacterium tuberculosis avium or Mycobacterium intracellulare; Infect relevant gastro-enteritis with campylobacter jejuni; The intestinal protozoa disease relevant with Cryptosporidium spp; Infect relevant odontogenic infection with viridans streptococci; Infect relevant persistence cough with bordetella pertussis; The gas gangrene relevant with clostridium perfringens or infection due to Bacteroides; Atherosclerosis or the cardiovascular disorder relevant with Hp or infection involving chlamydia pneumoniae; The ox respiratory disease relevant with pasteurella hemolytica, pasteurella multocida, Mycoplasma bovis or Bordetella spp; The cow intestinal disease relevant with bacillus coli or protozoal infections; Infect relevant dairy cow mastitis with streptococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, Klebsiella pneumoniae, corynebacterium or faecalis; The pig respiratory disease relevant with A.pleuro, pasteurella multocida or mycoplasma infection; Infect relevant chitling disease with the little snake bacterium of bacillus coli, Lawsonia intracellularis, salmonella or swine dysentery; The foot rot of cattle relevant with Fusobacterium spp; Infect relevant cow metritis with bacillus coli; Infect relevant cow hairy warts with actinomyces pseudonecrophorus or Bacteroides nodosus; Infect relevant cow pink-eye with hemophilus bovis; The cow premature labor relevant with protozoal infections; Infect relevant dog and cat urinary tract infection with bacillus coli; Infect relevant dog and cat skin skin and soft tissue infection with staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative staphylococcus or pasteurella multocida; With infect relevant dog and cat tooth or oral cavity infection with Alcaligenes, bacterioide, clostridium, enterobacteria, eubacterium, Peptostreptococcus, porphyromonas or prevotella.
13, the method for treatment Mammals, fish or birds illness, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this method comprises that claim 1 compound with significant quantity on the therapeutics is to described Mammals, fish or birds administration.
14, the method for claim 13, wherein said illness are to infect relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and mastoiditis with streptococcus pneumoniae, hemophilus influenzae, Moraxella catarrhalis, streptococcus aureus or peptostreptococcus; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis with streptococcus pyogenes, C family and G family suis, diphtheria clostridium or Actinobacillus haemolyticum; The respiratory tract infection relevant with mycoplasma pneumoniae, legionella pneumophilia, streptococcus pneumoniae, hemophilus influenzae or infection involving chlamydia pneumoniae; With streptococcus aureus, coagulase-positive staphylococci (being staphylococcus epidermidis, staphylococcus haemolyticus etc.), streptococcus pyogenes, streptococcus agalactiae, suis C-F family (minute-colony streptococci), viridans streptococci, minimum coryneform bacteria, clostridium or relevant non-concurrency skin and soft tissue infection, abscess and osteomyelitis and the lochiopyra of Bartonella henselae; Infect relevant uncomplicated acute urinary tract infection with Staphylococcus saprophyticus or faecalis; Urethritis and trachelitis; Infect relevant sexually transmitted disease (STD) with chlamydia trachomatis, Ducrey bacillus, Tyreponema pallidum, Ureaplasma urealyticum or Diplococcus gonorrhoeae; With streptococcus aureus (food poisoning and toxic shock syndrome) or A, the B toxin disease relevant with the streptococcal infection of C family; The ulcer relevant with helicobacter pylori infection; Infect relevant whole body heating syndrome with borrelia obermeieri; Infect relevant Lyme disease with Borrelia burgdofferi; Infect relevant conjunctivitis, keratitis and dacryocystitis with chlamydia trachomatis, Diplococcus gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, hemophilus influenzae or Listera spp; Infect relevant dissemination mycobacterium tuberculosis avium syndrome (MAC) with mycobacterium tuberculosis avium or Mycobacterium intracellulare; Infect relevant gastro-enteritis with campylobacter jejuni; The intestinal protozoa disease relevant with Cryptosporidium spp; Infect relevant odontogenic infection with viridans streptococci; Infect relevant persistence cough with bordetella pertussis; The gas gangrene relevant with clostridium perfringens or infection due to Bacteroides; Atherosclerosis or the cardiovascular disorder relevant with Hp or infection involving chlamydia pneumoniae; The ox respiratory disease relevant with pasteurella hemolytica, pasteurella multocida, Mycoplasma bovis or Bordetella spp; The cow intestinal disease relevant with bacillus coli or protozoal infections; Infect relevant dairy cow mastitis with streptococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, Klebsiella pneumoniae, corynebacterium or faecalis; The pig respiratory disease relevant with A.pleuro, pasteurella multocida or mycoplasma infection; Infect relevant chitling disease with the little snake bacterium of bacillus coli, Lawsonia intracellularis, salmonella or swine dysentery; The foot rot of cattle relevant with Fusobacterium spp; Infect relevant cow metritis with bacillus coli; Infect relevant cow hairy warts with actinomyces pseudonecrophorus or Bacteroides nodosus; Infect relevant cow pink-eye with hemophilus bovis; The cow premature labor relevant with protozoal infections; Infect relevant dog and cat urinary tract infection with bacillus coli; Infect relevant dog and cat skin skin and soft tissue infection with staphylococcus epidermidis, Staphylococcus intermedius, coagulase negative staphylococcus or pasteurella multocida; With infect relevant dog and cat tooth or oral cavity infection with Alcaligenes, bacterioide, clostridium, enterobacteria, eubacterium, Peptostreptococcus, porphyromonas or prevotella.
15, be used for the pharmaceutical composition of mammalian cancer treatment, this pharmaceutical composition comprises claim 1 compound and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
16, the pharmaceutical composition of claim 15, wherein said cancer is a nonsmall-cell lung cancer.
17, the method for treatment mammalian cancer comprises that 1 compound with significant quantity on the therapeutics is to described Mammals administration.
18, the method for claim 17, wherein said cancer is a nonsmall-cell lung cancer.
Or its pharmacy acceptable salt; Wherein
Dotted line between 10 and 11 is represented optional double bond;
A is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be N
3, R
10NH, R
10C (O) NH, R
10NHC (O) NH, R
10NHC (S) NH, R
10NHNHC (O) NH, R
10ONHC (O) NH or R
10OC (O) NH, R wherein
10Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl; Perhaps R
3Be R
14(C
2-C
4) alkynyl, R wherein
11Be (C
1-C
6) alkyl, (C
6-C
10) alkyl (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl; Perhaps R
3Be R
12R
13N, R wherein
12And R
13Be hydrogen, (C independently of one another
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl;
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
5-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement;
Its condition is if a is zero, then R
1Be hydrogen.
20, the pharmaceutical composition that is used for Mammals, fish or birds treatment for diseases, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this pharmaceutical composition comprises claim 19 compound and the pharmaceutically acceptable carrier of significant quantity on the therapeutics.
21, the method for treatment Mammals, fish or birds illness, these illnesss are selected from infectation of bacteria, protozoal infections and the illness relevant with infectation of bacteria or protozoal infections, and this method comprises that claim 19 compound with significant quantity on the therapeutics is to described Mammals, fish or birds administration.
22, following formula: compound
Wherein a is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl independently are selected from halogen, (C by one to three alternatively
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Substituting group replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be NH
2, N
3, O=C=N or S=C=N;
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three hydroxyl or halogen alternatively; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement.
Wherein a is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
3Be NH
2Or N
3
X is oxygen or NOR
16, R wherein
16Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are replaced by one to three substituting group alternatively, and substituting group is independently selected from halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2, R wherein
8And R
9Be hydrogen or optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement.
Wherein a is 0 or 1;
R
1Be hydrogen or optional by fluorine, cyano group, R
7, R
7O
2C, R
7C (O) NH and R
7S (O)
n(the C that replaces
1-C
10) alkyl, n wherein is 0,1 or 2, R
7Be (C
1-C
6) alkyl, (C
2-C
12) alkenyl, (C
2-C
12) alkynyl, (C
3-C
10) cycloalkyl (C
1-C
6) alkyl, (C
2-C
9) Heterocyclylalkyl (C
1-C
6) alkyl, (C
6-C
10) aryl (C
1-C
6) alkyl or (C
2-C
9) heteroaryl (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are alternatively by one to three halogen, (C
1-C
3) alkoxyl group, hydroxyl, nitro, cyano group, (C
6-C
10) aryl, (C
2-C
9) heteroaryl, R
8R
9N, R
8C (O), R
8C (O) O, R
8OC (O), R
8C (O) NH, R
8NHC (O), R
8R
9NC (O) and R
8OC (O)
2Replace R wherein
8And R
9Be hydrogen, optional quilt (C independently of one another
6-C
10) aryl or (C
2-C
9) (the C that replaces of heteroaryl
1-C
6) alkyl;
R
2Be hydrogen or hydroxy-protective group;
R
5Be hydrogen or methyl;
R
6Be hydrogen, (C
1-C
6) alkyl, (C
2-C
6) alkenyl, (C
2-C
6) alkynyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
1-C
6) alkylthio (C
1-C
6) alkyl, alkyl wherein, alkenyl, alkynyl or alkoxyl group are replaced by one to three substituting group alternatively, and substituting group is independently selected from hydroxyl and halogen; Perhaps R
6Be optional quilt (C
1-C
6) (the C that replaces of alkyl or halogen
3-C
10) cycloalkyl or (C
5-C
10) cycloalkenyl group; Perhaps R
6Be optional quilt (C
1-C
6) alkyl, (C
2-C
8) alkenyl, (C
2-C
8) alkynyl, (C
3-C
10) cycloalkyl, (C
5-C
10) (the C that replaces of cycloalkenyl group or aryl
2-C
8) Heterocyclylalkyl or (C
2-C
9) heteroaryl, aryl wherein is alternatively by alkyl, (C
1-C
6) the alkoxy or halogen replacement.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10683698P | 1998-11-03 | 1998-11-03 | |
US60/106,836 | 1998-11-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1376160A true CN1376160A (en) | 2002-10-23 |
Family
ID=22313524
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN99812941A Pending CN1376160A (en) | 1998-11-03 | 1999-10-18 | Novel macrolide antibiotics |
Country Status (34)
Country | Link |
---|---|
US (3) | US20020040007A1 (en) |
EP (1) | EP1124837A2 (en) |
JP (1) | JP4043191B2 (en) |
KR (1) | KR20010083944A (en) |
CN (1) | CN1376160A (en) |
AP (1) | AP2001002131A0 (en) |
AU (1) | AU5995299A (en) |
BG (1) | BG105543A (en) |
BR (1) | BR9914998A (en) |
CA (1) | CA2349338C (en) |
CO (1) | CO5140110A1 (en) |
CZ (1) | CZ20011512A3 (en) |
EA (1) | EA200100396A1 (en) |
EE (1) | EE200100245A (en) |
GT (1) | GT199900192A (en) |
HK (1) | HK1049010A1 (en) |
HR (1) | HRP20010306A2 (en) |
HU (1) | HUP0104192A3 (en) |
ID (1) | ID28286A (en) |
IL (1) | IL142628A0 (en) |
IS (1) | IS5919A (en) |
MA (1) | MA26703A1 (en) |
NO (1) | NO20012155L (en) |
OA (1) | OA11670A (en) |
PA (1) | PA8485101A1 (en) |
PE (1) | PE20001289A1 (en) |
PL (1) | PL348114A1 (en) |
SK (1) | SK5812001A3 (en) |
SV (1) | SV1999000188A (en) |
TN (1) | TNSN99205A1 (en) |
TR (4) | TR200200434T2 (en) |
UY (1) | UY25780A1 (en) |
WO (1) | WO2000026224A2 (en) |
ZA (1) | ZA200103289B (en) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AP9801420A0 (en) * | 1998-01-02 | 1998-12-31 | Pfizer Prod Inc | Novel macrolides. |
CA2349338C (en) | 1998-11-03 | 2005-12-06 | Pfizer Products Inc. | Novel macrolide antibiotics |
ID30233A (en) | 1999-01-27 | 2001-11-15 | Pfizer Prod Inc | ANTIBIOTICS OF TETOLIDA |
US6590083B1 (en) | 1999-04-16 | 2003-07-08 | Ortho-Mcneil Pharmaceutical, Inc. | Ketolide antibacterials |
US6514944B2 (en) | 1999-04-16 | 2003-02-04 | Kosan Biosciences, Inc. | Macrolide antiinfective agents |
US6939861B2 (en) | 1999-04-16 | 2005-09-06 | Kosan Biosciences, Inc. | Amido macrolides |
MXPA01010521A (en) | 1999-04-16 | 2003-08-19 | Johnson & Johnson | Ketolide antibacterials. |
DE60030847T2 (en) | 1999-04-16 | 2007-04-19 | Kosan Biosciences, Inc., Hayward | ANTI-INFECTIOUS MAKROLIDE DERIVATIVES |
US6451768B1 (en) | 1999-04-16 | 2002-09-17 | Kosan Biosciences, Inc. | Macrolide antiinfective agents |
CZ20013733A3 (en) | 1999-05-24 | 2002-11-13 | Pfizer Products Inc. | 13-Methyl erythromycin derivatives |
EP1114826A3 (en) * | 1999-12-29 | 2001-10-31 | Pfizer Products Inc. | Novel antibacterial and prokinetic macrolides |
EP1146051A3 (en) * | 2000-04-10 | 2001-10-31 | Pfizer Products Inc. | Erythromycin A derivatives |
ATE271062T1 (en) | 2000-06-30 | 2004-07-15 | Pfizer Prod Inc | MACROLIDE ANTIBIOTICS |
RU2397987C2 (en) * | 2004-07-28 | 2010-08-27 | Рэнбакси Лабораториз Лимитед | Ketolide derivatives as antibacterial agents |
US20090170790A1 (en) * | 2004-10-25 | 2009-07-02 | Biswajit Das | Ketolide derivatives as antibacterial agents |
CN101120011A (en) * | 2004-12-21 | 2008-02-06 | 辉瑞产品公司 | Macrolides |
EP1960413A2 (en) * | 2005-11-23 | 2008-08-27 | Ranbaxy Laboratories Limited | Macrolides derivatives as antibacterial agents |
EP1957508A2 (en) * | 2005-11-23 | 2008-08-20 | Ranbaxy Laboratories Limited | Ketolide derivatives as antibacterial agents |
US7801502B2 (en) * | 2006-12-18 | 2010-09-21 | Aai Corporation | Method for implementing continuous radio frequency (RF) alignment in advanced electronic warfare (EW) signal stimulation systems |
US8409628B2 (en) | 2010-02-04 | 2013-04-02 | Penguin IP Holdings, Inc. | Methods and compositions for oxygenation of skin to treat skin disorders |
US8900601B2 (en) | 2010-03-31 | 2014-12-02 | Jennifer Bartels | Permeable mixtures, methods and compositions for the skin |
NZ713615A (en) * | 2013-05-01 | 2020-05-29 | Neoculi Pty Ltd | Methods for treating bacterial infections |
RU2537143C1 (en) * | 2013-11-08 | 2014-12-27 | Государственное научное учреждение Ставропольский научно-исследовательский институт животноводства и кормопроизводства РАСХН | Preparation for treatment and prevention of mastitis in cows |
WO2018080072A2 (en) * | 2016-10-27 | 2018-05-03 | 한국생명공학연구원 | Novel macrolide-based compound, method for producing same, and pharmaceutical composition for preventing or treating malaria and containing same as active ingredient |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
YU43006B (en) * | 1981-03-06 | 1989-02-28 | Pliva Pharm & Chem Works | Process for preparing n-methyl-11-aza-10-deoxo-10-dihydro erythromycin and derivatives thereof |
US4474768A (en) * | 1982-07-19 | 1984-10-02 | Pfizer Inc. | N-Methyl 11-aza-10-deoxo-10-dihydro-erytromycin A, intermediates therefor |
IL114589A (en) * | 1990-11-21 | 1999-12-22 | Roussel Uclaf | Intermediates for the preparation of erythromycin derivatives |
US5527780A (en) | 1992-11-05 | 1996-06-18 | Roussel Uclaf | Erythromycin derivatives |
FR2697524B1 (en) * | 1992-11-05 | 1994-12-23 | Roussel Uclaf | New erythromycin derivatives, their preparation process and their use as drugs. |
US5332807A (en) | 1993-04-14 | 1994-07-26 | Merck & Co., Inc. | Process of producing 8A- and 9A-azalide antibiotics |
FR2702480B1 (en) * | 1993-03-09 | 1995-04-28 | Roussel Uclaf | New erythromycin derivatives, their preparation process and their use as drugs. |
HRP931480B1 (en) | 1993-12-08 | 1997-08-31 | Sour Pliva | 9a-N-(N'-CARBAMONYL) and 9a-N-(N'-THIOCARBAMONYL) DERIVATES OF 9-DEOXO-9a-HOMOERYTHROMYCIN A |
HRP950145A2 (en) | 1995-03-27 | 1997-08-31 | Sour Pliva | New compounds of the secomacrolide and secoazalide class and a process for the preparation thereof |
HN1996000101A (en) | 1996-02-28 | 1997-06-26 | Inc Pfizer | COMBINED THERAPY FOR OSTEOPOROSIS |
EP0918783A1 (en) * | 1996-05-07 | 1999-06-02 | Abbott Laboratories | 6-o-substituted erythromycins and method for making them |
ES2337424T3 (en) | 1996-07-05 | 2010-04-23 | Biotica Technology Limited | SYNTHETIC POLYCHETTE GENE I HYBRID. |
UA51730C2 (en) * | 1996-09-04 | 2002-12-16 | Ебботт Лабораторіз | 6-0-substituted ketolides having antibacterial activity |
PT1291353E (en) * | 1996-09-04 | 2005-10-31 | Abbott Lab | 6-O-SUBSTITUTED CETOLIDES HAVING ANTIBACTERIAL ACTIVITY |
HRP960497B1 (en) | 1996-10-28 | 2003-08-31 | Pliva Pharm & Chem Works | 9-n-ethenyl derivatives of 9(s)-erythromycylamine |
HN1998000074A (en) | 1997-06-11 | 1999-01-08 | Pfizer Prod Inc | DERIVATIVES FROM MACROLIDES C-4 SUBSTITUTED |
US6407074B1 (en) | 1997-06-11 | 2002-06-18 | Pfizer Inc | C-4″-substituted macrolide derivatives |
EP0895999A1 (en) | 1997-08-06 | 1999-02-10 | Pfizer Products Inc. | C-4" substituted macrolide antibiotics |
US6339063B1 (en) | 1997-09-10 | 2002-01-15 | Merck & Co., Inc. | 9a-azalides as veterinary antimicrobial agents |
PT1036083E (en) | 1997-10-16 | 2004-10-29 | Pliva Pharm & Chem Works | NEW 9A-AZALIDOS |
DK0941998T3 (en) | 1998-03-03 | 2004-09-20 | Pfizer Prod Inc | 3,6-ketal macrolide antibiotics |
CA2349338C (en) | 1998-11-03 | 2005-12-06 | Pfizer Products Inc. | Novel macrolide antibiotics |
CZ20013733A3 (en) | 1999-05-24 | 2002-11-13 | Pfizer Products Inc. | 13-Methyl erythromycin derivatives |
EP1114826A3 (en) | 1999-12-29 | 2001-10-31 | Pfizer Products Inc. | Novel antibacterial and prokinetic macrolides |
EP1122261A3 (en) | 2000-01-31 | 2001-09-26 | Pfizer Products Inc. | 13 and 14-membered antibacterial macrolides |
ATE271062T1 (en) | 2000-06-30 | 2004-07-15 | Pfizer Prod Inc | MACROLIDE ANTIBIOTICS |
WO2003004509A2 (en) | 2001-07-03 | 2003-01-16 | Chiron Corporation | C12 modified erythromycin macrolides and ketolides having antibacterial activity |
-
1999
- 1999-10-18 CA CA002349338A patent/CA2349338C/en not_active Expired - Fee Related
- 1999-10-18 TR TR2002/00434T patent/TR200200434T2/en unknown
- 1999-10-18 PL PL99348114A patent/PL348114A1/en not_active Application Discontinuation
- 1999-10-18 EP EP99971424A patent/EP1124837A2/en not_active Withdrawn
- 1999-10-18 EA EA200100396A patent/EA200100396A1/en unknown
- 1999-10-18 CZ CZ20011512A patent/CZ20011512A3/en unknown
- 1999-10-18 WO PCT/IB1999/001701 patent/WO2000026224A2/en not_active Application Discontinuation
- 1999-10-18 EE EEP200100245A patent/EE200100245A/en unknown
- 1999-10-18 JP JP2000579612A patent/JP4043191B2/en not_active Expired - Fee Related
- 1999-10-18 TR TR2001/01241T patent/TR200101241T2/en unknown
- 1999-10-18 TR TR2002/00435T patent/TR200200435T2/en unknown
- 1999-10-18 IL IL14262899A patent/IL142628A0/en unknown
- 1999-10-18 SK SK581-2001A patent/SK5812001A3/en unknown
- 1999-10-18 BR BR9914998-2A patent/BR9914998A/en not_active IP Right Cessation
- 1999-10-18 OA OA1200100102A patent/OA11670A/en unknown
- 1999-10-18 HU HU0104192A patent/HUP0104192A3/en unknown
- 1999-10-18 CN CN99812941A patent/CN1376160A/en active Pending
- 1999-10-18 KR KR1020017005535A patent/KR20010083944A/en not_active Application Discontinuation
- 1999-10-18 AP APAP/P/2001/002131A patent/AP2001002131A0/en unknown
- 1999-10-18 AU AU59952/99A patent/AU5995299A/en not_active Abandoned
- 1999-10-18 ID IDW20010956D patent/ID28286A/en unknown
- 1999-10-18 TR TR2002/00436T patent/TR200200436T2/en unknown
- 1999-10-29 PE PE1999001084A patent/PE20001289A1/en not_active Application Discontinuation
- 1999-10-29 UY UY25780A patent/UY25780A1/en unknown
- 1999-10-29 SV SV1999000188A patent/SV1999000188A/en not_active Application Discontinuation
- 1999-11-02 MA MA25832A patent/MA26703A1/en unknown
- 1999-11-02 TN TNTNSN99205A patent/TNSN99205A1/en unknown
- 1999-11-02 PA PA19998485101A patent/PA8485101A1/en unknown
- 1999-11-03 CO CO99069359A patent/CO5140110A1/en unknown
- 1999-11-03 GT GT199900192A patent/GT199900192A/en unknown
-
2001
- 2001-04-17 IS IS5919A patent/IS5919A/en unknown
- 2001-04-23 ZA ZA200103289A patent/ZA200103289B/en unknown
- 2001-04-30 HR HR20010306A patent/HRP20010306A2/en not_active Application Discontinuation
- 2001-05-02 NO NO20012155A patent/NO20012155L/en not_active Application Discontinuation
- 2001-05-29 BG BG105543A patent/BG105543A/en unknown
- 2001-10-01 US US09/969,486 patent/US20020040007A1/en not_active Abandoned
-
2002
- 2002-07-24 US US10/206,652 patent/US6835716B2/en not_active Expired - Fee Related
-
2003
- 2003-02-18 HK HK03101144.0A patent/HK1049010A1/en unknown
-
2004
- 2004-07-21 US US10/896,293 patent/US7071170B2/en not_active Expired - Fee Related
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1376160A (en) | Novel macrolide antibiotics | |
CN1145636C (en) | C-4'-substituted macrolide derivatives | |
CN1172947C (en) | 4'-substituted-9-deoxo-9A-AZA-9A-homoerythromycin a derivatives | |
CN1326460A (en) | B-membered azalides and their use as antibiotic agents | |
JP3947360B2 (en) | Ketolide antibiotic | |
CN1284081A (en) | Novel macrolides compounds | |
US6664238B1 (en) | Carbamate and carbazate ketolide antibiotics | |
CN1259135A (en) | 9-oxime erythromycin derivatives | |
CN1244532A (en) | 3,6-aldehyde acetal and enol ether large ring lactone vitamine | |
WO1999021866A1 (en) | 9-amino-3-keto erythromycin derivatives | |
CN1227258C (en) | Use of azalide antibiotic compositions for treating or preventing bacterial or protozoal infection in mammals | |
JP2000119294A (en) | New macrolide derivative | |
WO1999021865A1 (en) | Tricyclic erythromycin derivatives | |
JP2001213895A (en) | New antibacterial and prokinetic macrolide | |
JP3587380B2 (en) | Macrolide antibiotics | |
EP1122261A2 (en) | 13 and 14-membered antibacterial macrolides | |
CN1780847A (en) | Crystal forms of azithromycin | |
CA2270124C (en) | 9a,11b-dehydro derivatives of 9-oxime-3-keto-6-0-methylerythromycin | |
EP1298138B1 (en) | Carbamate and Carbazate Ketolide Antibiotics | |
MXPA01001212A (en) | 13 and 14-membered antibacterial macrolides | |
EP1749832A2 (en) | Carbamate and carbazate ketolide antibiotics | |
MXPA01004418A (en) | Novel macrolide antibiotics |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1049010 Country of ref document: HK |